tbuckley/cabot-search huggingface dataset:
Programming cytomegalovirus as an HIV vaccine
Authors: Louis J. Picker, Jeffrey D. Lifson, Michael Gale, Scott G. Hansen, Klaus Früh
Journal: Trends in Immunology (2023)

The initial development of cytomegalovirus (CMV) as a vaccine vector for HIV/simian immunodeficiency virus (SIV) was predicated on its potential to pre-position high-frequency, effector-differentiated, CD8+ T cells in tissues for immediate immune interception of nascent primary infection. This goal was achieved and also led to the unexpected discoveries that non-human primate (NHP) CMVs can be programmed to differentially elicit CD8+ T cell responses that recognize viral peptides via classical MHC-Ia, and/or MHC-II, and/or MHC-E, and that MHC-E-restricted CD8+ T cell responses can uniquely mediate stringent arrest and subsequent clearance of highly pathogenic SIV, an unprecedented type of vaccine-mediated protection. These discoveries delineate CMV vector-elicited MHC-E-restricted CD8+ T cells as a functionally distinct T cell response with the potential for superior efficacy against HIV-1, and possibly other infectious agents or cancers.
Clinical and prognostic associations of autoantibodies recognizing adrenergic/muscarinic receptors in patients with heart failure
Authors: George Markousis-Mavrogenis, Waldemar B Minich, Ali A Al-Mubarak, Stefan D Anker, John G F Cleland, Kenneth Dickstein, Chim C Lang, Leong L Ng, Nilesh J Samani, Faiez Zannad, Marco Metra, Petra Seemann, Antonia Hoeg, Patricio Lopez, Dirk J van Veldhuisen, Rudolf A de Boer, Adriaan A Voors, Peter van der Meer, Lutz Schomburg, Nils Bomer
Journal: Cardiovascular Research (2023)

The importance of autoantibodies (AABs) against adrenergic/muscarinic receptors in heart failure (HF) is not well-understood. We investigated the prevalence and clinical/prognostic associations of four AABs recognizing the M2-muscarinic receptor or the β1-, β2-, or β3-adrenergic receptor in a large and well-characterized cohort of patients with HF.Serum samples from 2256 patients with HF from the BIOSTAT-CHF cohort and 299 healthy controls were analysed using newly established chemiluminescence immunoassays. The primary outcome was a composite of all-cause mortality and HF rehospitalization at 2-year follow-up, and each outcome was also separately investigated. Collectively, 382 (16.9%) patients and 37 (12.4%) controls were seropositive for ≥1 AAB (P = 0.045). Seropositivity occurred more frequently only for anti-M2 AABs (P = 0.025). Amongst patients with HF, seropositivity was associated with the presence of comorbidities (renal disease, chronic obstructive pulmonary disease, stroke, and atrial fibrillation) and with medication use. Only anti-β1 AAB seropositivity was associated with the primary outcome [hazard ratio (95% confidence interval): 1.37 (1.04-1.81), P = 0.024] and HF rehospitalization [1.57 (1.13-2.19), P = 0.010] in univariable analyses but remained associated only with HF rehospitalization after multivariable adjustment for the BIOSTAT-CHF risk model [1.47 (1.05-2.07), P = 0.030]. Principal component analyses showed considerable overlap in B-lymphocyte activity between seropositive and seronegative patients, based on 31 circulating biomarkers related to B-lymphocyte function.AAB seropositivity was not strongly associated with adverse outcomes in HF and was mostly related to the presence of comorbidities and medication use. Only anti-β1 AABs were independently associated with HF rehospitalization. The exact clinical value of AABs remains to be elucidated.
Progress for patients with melanoma brain metastases
Authors: Paul W Sperduto, April K S Salama, Carey Anders
Journal: Neuro-Oncology (2023)

Journal Article Progress for patients with melanoma brain metastases Get access Paul W Sperduto, Paul W Sperduto Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, USA Corresponding Author: Paul W. Sperduto, MD, MPP, FASTRO, Department of Radiation Oncology, Duke University School of Medicine, Durham, NC, USA (paul.sperduto@duke.edu). Search for other works by this author on: Oxford Academic PubMed Google Scholar April K S Salama, April K S Salama Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Carey Anders Carey Anders Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Neuro-Oncology, Volume 25, Issue 7, July 2023, Pages 1321–1322, https://doi.org/10.1093/neuonc/noad050 Published: 08 March 2023 Article history Published: 08 March 2023 Corrected and typeset: 22 March 2023
A new path to alternative lengthening of telomeres?
Authors: Oren J Becher
Journal: Neuro-Oncology (2023)

Journal Article A new path to alternative lengthening of telomeres? Get access Oren J Becher Oren J Becher Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York, USADepartment of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USATisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA Corresponding Author: Oren J. Becher, MD, Chief, The Jack Martin Fund Division of Pediatric Hematology-Oncology, Steven Ravitch Chair in Pediatric Hematology-Oncology, Mount Sinai Kravis Children's Hospital, Professor of Pediatrics and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, USA (oren.becher@mssm.edu). https://orcid.org/0000-0003-4016-8492 Search for other works by this author on: Oxford Academic PubMed Google Scholar Neuro-Oncology, Volume 25, Issue 7, July 2023, Pages 1343–1344, https://doi.org/10.1093/neuonc/noad054 Published: 08 March 2023 Article history Published: 08 March 2023 Corrected and typeset: 31 March 2023
Abstract 5494: Pharmacokinetics and Pharmacodynamics of Ticagrelor in Patients With Stable Coronary Artery Disease
Authors: Steen E Husted, Paul Gurbel, Robert F Storey, Kevin Bliden, Lene Høimark, Mark J Antonino, Elisabeth Mahla, Udaya Tantry, Kathleen Butler, Cheryl Wei, Renli Teng
Journal: Circulation (2009)

Background: Ticagrelor (T), the first reversibly binding oral P2Y 12 receptor antagonist, has been evaluated in patients with ACS. Reversible inhibition is desirable for patients who experience bleeding complications or require invasive procedures. Methods: Two studies examined the pharmacokinetics (PK) of T in patients with stable coronary artery disease (CAD). In the multicenter, randomized, double-blind parallel group ONSET-OFFSET study, patients with stable CAD currently receiving aspirin (75–100 mg) were randomized to doses of T (180 mg load, 90 mg bid maintenance [n=57]), clopidogrel (C) (600 mg load, 75 mg qd maintenance [n=54]) or placebo (n=12) for 6 weeks. PK of T and AR-C124910XX (AR), an active metabolite, were evaluated following loading and last maintenance doses. In RESPOND (2-way crossover design), patients with stable CAD classified as C non-responders (n=41) and responders (n=57) were randomized to 14 days treatment with C 600 mg load/75 mg qd or T 180 mg loading/90 mg bid with no washout between treatments. On Days 1 and 14, t max , C max and AUC 0 – 8 of T and AR were evaluated. Results: In ONSET-OFFSET, C max , t max and t 1/2 values of T (733 ng/mL, 2 h, and 10.2 h, respectively) and AR (210.3 ng/mL, 2.1 h, and 12.8 h) at 90 mg bid were comparable to those seen previously in healthy subjects. E max estimates of final extent IPA (%) vs plasma concentration curves of T and AR were 98.6% and 91.8%, respectively. Trough plasma T (304.6 ng/mL) and AR (120.7 ng/mL) concentrations were 4 and 6 times higher than the respective EC 50 estimates (58.6 ng/mL and 15.7 ng/mL, respectively). In RESPOND, mean C max and AUC 0 – 8 of T following 2-week maintenance doses were similar between C responders (724.2 ng/mL and 3982.7 ng·h/mL) and non-responders (764.4 ng/mL and 3985.2 ng·h/mL). PK of T were not affected when T was administered 24 h post C dosing. Conclusions: This dosing regimen of T and AR effectively inhibited platelet aggregation; trough plasma levels of T (90 mg bid) and AR were sufficient to achieve high IPA. The pharmacodynamic response followed PK. Importantly, PK of T administered after crossover from C were unchanged and not affected by patient responsiveness to C.
Nutrition and Poverty in Preschool Children
Authors: Paul Zee
Journal: JAMA (1970)

The effect of poverty on nutrition of preschool children was evaluated in 300 children randomly selected from 2,427 black children of poverty families living in south Memphis. Half of the children were found to be below the 25th percentile for height and weight on anthropometric charts. Anemia was common; 28% of the children less than 3 years of age had hemoglobin levels below 10 gm/100 ml, and 25% of the children older than 3 years had levels below 11 gm/100 ml. The extremely low family incomes and information gained by home visits indicated that lack of food was the main cause of growth retardation and anemia.
Normal Viral and Bacterial Flora of the Human Small and Large Intestine
Authors: M. H. Kalser, R. Cohen, I. Arteaga, E. Yawn, L. Mayoral, W. R. Hoffert, D. Frazier
Journal: New England Journal of Medicine (1966)

IN recent years there has been an ever increasing interest in the human enteric flora in normal and pathologic states.1 2 3 4 Current reports have focused on germ-free animals,5 6 7 the effect of suppressing the enteric flora with antibiotics,8 9 10 the relation of intestinal bacteria and leukocytes,6 , 11 the effect of malnutrition on the ecology of the gut12 and the growing recognition of the genus bacteroides as being an important inhabitant of the normal adult colon.5 , 13 Renewed interest in bacterial overgrowth of the small bowel and its association with hematologic syndromes, malabsorptive states and morphologic mucosal changes is again evident.9 , 10 , 14 , 15 Quantitative bacterial change occurring in . . .
The Relationship of Cigarette Smoking to Coronary Heart Disease
Authors: Joseph T. Doyle, Thomas R. Dawber, William B. Kannel, Sandra H. Kinch, Harold A. Kahn
Journal: JAMA (1964)

The relationship of smoking habit to total mortality and to the incidence of new manifestations of coronary heart disease (CHD) has been examined in 2,282 middle-aged men under medical surveillance for ten years in Framingham, Mass, and 1,838 middle-aged men followed for eight years in Albany, NY. It was found that in men who report habitual consumption of 20 or more cigarettes per day the risk of myocardial infarction was about three times greater than in nonsmokers, former cigarette smokers, or pipe and cigar smokers. No relationship was shown between smoking habit and angina pectoris when this symptom was the sole manifestation of CHD. The association between heavy cigarette smoking and increased morbidity and mortality from CHD was unexplained, although it appeared to be relatively immediate. It is inferred that stopping cigarette smoking lessens the risk of CHD.
Clinical, Immunologic, and Serologic Findings in Men at Risk for Acquired Immunodeficiency Syndrome
Authors: William Lang
Journal: JAMA (1987)

Forty-nine percent of homosexual/bisexual men were positive for antibody to the human immunodeficiency virus (HIV) in a population-based probability sample of 1034 single men recruited from San Francisco. All heterosexual men were negative. Among seropositive men, marked lymphadenopathy was present in 29%, and 16% had at least two other symptoms or signs suggestive of HIV infection. However, lymphadenopathy alone failed to indicate severity of immune impairment. The occurrence of two or more clinical signs and symptoms, except for marked lymphadenopathy, correlated with HIV infection, diminished skin test reactivity, and reduction in Leu 3a T cells. Twenty-nine percent of seropositive men had fewer than 400 absolute Leu 3a T helper cells per microliter (&lt;0.4×10<sup>9</sup>/L). Seronegative homosexual/bisexual men did not differ from heterosexual men in any clinical or laboratory variables except for increased numbers of suppressor Leu 2a T suppressor cells per microliter. (<i>JAMA</i>1987;257:326-330)
IMMUNOCHEMICAL STUDIES ON BLOOD GROUPS
Authors: Elvin A. Kabat, Aaron Bendich, Ada E. Bezer
Journal: The Journal of Experimental Medicine (1946)

1. The microquantitative precipitin method can be used to compare the relative activity of different preparations of the blood group A substance from hog stomachs and to study the effect of chemical treatment upon its stability. 2. With samples of about 25 µg. antibody nitrogen, an error of ±1.7 µg. antibody nitrogen will result in an error of ±12 per cent in the estimation of the amount of A substance. 3. The blood group A substance showed no significant loss of activity at 37°C. after 48 hours at pH 1.07 to 10.7 or after 2 hours at 100°C. over a pH range from 2.97 to 7.58. Exposure at 100°C. at pH 1.03 or at 9.03 or higher resulted in loss of activity. Parallel results were obtained by the hemagglutination inhibition and quantitative precipitin methods. 4. The solubility of specific precipitates of the blood group A substance from hog stomach and its homologous antibody formed in man was found to be about 1.6 µg. antibody N/ml. 5. A comparison is given of the chemical properties and activity of blood group A substances obtained by several procedures from pools of hog stomachs.
How White and African Americans View Their Health and Social Problems
Authors: Robert J. Blendon
Journal: JAMA (1995)

DESPITE increases in expenditures and expansions of many US health and social welfare programs and institutions, racial disparities persist in many aspects of American society. Particularly troubling is the reality that the health of our nation's population differs so greatly by race. A number of studies in recent years have documented substantial differences between white and African Americans in health status, morbidity and mortality, access to health services, and perceptions of quality in health care services received.<sup>1-9</sup> Consistent with these reports of differences in overall health, national opinion surveys show that African Americans are more likely than whites to rate the health services in their communities as fair or poor (46% and 23%)<sup>10</sup>; our study also indicates that African Americans are more likely to state that the health system in this country needs to be completely rebuilt (42% vs 31%). This disparity between the assessments of African Americans
RNA Splicing and Genes
Authors: Phillip A. Sharp
Journal: JAMA (1988)

The splicing of long transcripts of RNA (copied from DNA in the cell nucleus) into smaller, specific mRNA (ready for export to the protein-producing machinery in the cytoplasm) is an important event in the regulation of gene expression in eukaryotic cells. The splicing reaction occurs as a late step in the nuclear pathway for synthesis of mRNAs. This pathway commences with initiation of transcription by RNA polymerase II and probably involves an integrated series of steps each dependent on previous events. Splicing of precursors to mRNAs involves the formation of a spliceosome complex containing the 5' and 3' splice sites. This complex contains the evolutionarily highly conserved small nuclear RNAs (snRNAs) U2, U4, U5, and U6. The most abundant snRNA, U1, is required to form the spliceosome and may be a part of the spliceosome. Analogues of these snRNAs have been identified in yeast. Assembly of the spliceosome probably involves the binding of a multi-snRNA complex containing U4, U5, and U6 snRNAs. Several observations suggest that the association of snRNAs in such complexes is quite dynamic. It is argued that the snRNAs in the spliceosome form a catalytic RNA structure that is responsible for the cleavage and ligation steps during splicing. (<i>JAMA</i>1988;260:3035-3041)
Calcium and Phosphate Requirements of Preterm Infants Who Require Prolonged Hyperalimentation
Authors: Philip J. Knight
Journal: JAMA (1980)

Preterm infants require large amounts of calcium and phosphate to maintain skeletal mineralization during prolonged hyperalimentation. It is impossible to supply the amount of calcium and phosphate normally acquired transplacentally (150 mg/kg/day of calcium and 80 mg/kg/day of phosphate) with reasonable volumes of a single hyperalimentation solution of a physiological pH. We recently encountered calcium phosphate precipitates plugging our hyperalimentation catheters as we tried to raise the calcium concentration above 20 mEq of calcium per liter of hyperalimentation solution. Such a solution supplies 50 mg/kg/day of calcium when run at 125 mL/kg/day. In an attempt to circumvent this problem, we are currently using two hyperalimentation solutions—one high in calcium and the other high in phosphates—run alternately for 12-hour periods. This regimen supplies 80 mg/kg/day of calcium. (<i>JAMA</i>243:1244-1246, 1980)
Thrombolytic Therapy of Acute Myocardial Infarction
Authors: Andrew J. Doorey
Journal: JAMA (1992)

<h3>Objective.</h3> —To assess the use of thrombolytic therapy for acute myocardial infarction, evaluating whether inclusion and exclusion criteria should be altered as well as the public health implications of any such alterations. <h3>Data Sources.</h3> —Data obtained were from English-language articles on the use of thrombolytic therapy in acute myocardial infarction. Articles that reported on inclusion and exclusion criteria as well as specific complications of this therapy were specifically sought. The review included articles under the terms<i>thrombolytic therapy and acute myocardial infarction</i>in the National Library of Medicine's MEDLINE database. <h3>Study Selection.</h3> —Studies selected for detailed review were those reporting specifics about inclusion and exclusion criteria and efficacy. Data extraction guidelines for assessing data quality included study size, patient population, detail of patient information acquired, and consecutive patient enrollment. <h3>Data Synthesis.</h3> —Thrombolytic therapy can provide substantial decrements of morbidity and mortality of acute myocardial infarction in the subset of patients who receive this therapy, but is underused in the United States. Advanced age per se should not be an exclusion criterion. Improvements can be made in electrocardiographic diagnosis of acute myocardial infarction. Many of the clinical conditions initially excluded from thrombolytic consideration, such as hypertension or having received cardiopulmonary resuscitation, are only relative contraindications. The benefit/risk ratio in treatment of these patients is often acceptable. Several well-documented points of delay from onset of symptoms to treatment can be minimized, and accelerated therapy can result in a reduction in mortality rates. <h3>Conclusion.</h3> —Significant public health benefits will result from greater use of thrombolytic therapy in acute myocardial infarction. (<i>JAMA</i>. 1992;268:3108-3114)
Treatment of Pyelonephritis
Authors: William R. McCabe, George Gee Jackson
Journal: New England Journal of Medicine (1965)

EFFECTIVE therapy for most bacterial infections has been developed since the advent of potent antimicrobial agents. Chronic pyelonephritis, however, has been notably refractory to permanent cure. Autopsy studies have demonstrated no decrease in the incidence of pyelonephritis since the introduction of antibiotics.1 It has been estimated that prolonged freedom from infection is achieved in as few as 10 per cent of these patients.2 In two earlier investigations bacteriuria was eliminated in almost all patients with chronic pyelonephritis during treatment, but only 50 per cent remained free of infection after therapy.3 , 4 Variable cure rates have been reported in different series in . . .
Organ-specific fuel rewiring in acute and chronic hypoxia redistributes glucose and fatty acid metabolism
Authors: Ayush D. Midha, Yuyin Zhou, Bruno B. Queliconi, Alec M. Barrios, Augustinus G. Haribowo, Brandon T.L. Chew, Cyril O.Y. Fong, Joseph E. Blecha, Henry VanBrocklin, Youngho Seo, Isha H. Jain
Journal: Cell Metabolism (2023)
FGF21 counteracts alcohol intoxication by activating the noradrenergic nervous system
Authors: Mihwa Choi, Marc Schneeberger, Wei Fan, Abhijit Bugde, Laurent Gautron, Kevin Vale, Robert E. Hammer, Yuan Zhang, Jeffrey M. Friedman, David J. Mangelsdorf, Steven A. Kliewer
Journal: Cell Metabolism (2023)

Animals that consume fermenting fruit and nectar are at risk of exposure to ethanol and the detrimental effects of inebriation. In this report, we show that the hormone FGF21, which is strongly induced by ethanol in murine and human liver, stimulates arousal from intoxication without changing ethanol catabolism. Mice lacking FGF21 take longer than wild-type littermates to recover their righting reflex and balance following ethanol exposure. Conversely, pharmacologic FGF21 administration reduces the time needed for mice to recover from ethanol-induced unconsciousness and ataxia. FGF21 did not counteract sedation caused by ketamine, diazepam, or pentobarbital, indicating specificity for ethanol. FGF21 mediates its anti-intoxicant effects by directly activating noradrenergic neurons in the locus coeruleus region, which regulates arousal and alertness. These results suggest that this FGF21 liver-brain pathway evolved to protect against ethanol-induced intoxication and that it might be targeted pharmaceutically for treating acute alcohol poisoning.
Estradiol regulates leptin sensitivity to control feeding via hypothalamic Cited1
Authors: Ismael González-García, Elena García-Clavé, Alberto Cebrian-Serrano, Ophélia Le Thuc, Raian E. Contreras, Yanjun Xu, Tim Gruber, Sonja C. Schriever, Beata Legutko, Jutta Lintelmann, Jerzy Adamski, Wolfgang Wurst, Timo D. Müller, Stephen C. Woods, Paul T. Pfluger, Matthias H. Tschöp, Alexandre Fisette, Cristina García-Cáceres
Journal: Cell Metabolism (2023)

Highlights•Global and hypothalamic Cited1 loss exacerbates diet-induced obesity in female mice•Cited1 is highly enriched in estradiol-sensitive melanocortin neurons•Hypothalamic Cited1 molecularly links the effects of E2 and leptin on food intake•Cited1 in PomcARC neurons acts as a downstream co-factor for E2-leptin signalingSummaryUntil menopause, women have a lower propensity to develop metabolic diseases than men, suggestive of a protective role for sex hormones. Although a functional synergy between central actions of estrogens and leptin has been demonstrated to protect against metabolic disturbances, the underlying cellular and molecular mechanisms mediating this crosstalk have remained elusive. By using a series of embryonic, adult-onset, and tissue/cell-specific loss-of-function mouse models, we document an unprecedented role of hypothalamic Cbp/P300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 1 (Cited1) in mediating estradiol (E2)-dependent leptin actions that control feeding specifically in pro-opiomelanocortin (Pomc) neurons. We reveal that within arcuate Pomc neurons, Cited1 drives leptin's anorectic effects by acting as a co-factor converging E2 and leptin signaling via direct Cited1-ERα-Stat3 interactions. Together, these results provide new insights on how melanocortin neurons integrate endocrine inputs from gonadal and adipose axes via Cited1, thereby contributing to the sexual dimorphism in diet-induced obesity.Graphical abstract
The global burden of metabolic disease: Data from 2000 to 2019
Authors: Nicholas W.S. Chew, Cheng Han Ng, Darren Jun Hao Tan, Gwyneth Kong, Chaoxing Lin, Yip Han Chin, Wen Hui Lim, Daniel Q. Huang, Jingxuan Quek, Clarissa Elysia Fu, Jieling Xiao, Nicholas Syn, Roger Foo, Chin Meng Khoo, Jiong-Wei Wang, Georgios K. Dimitriadis, Dan Yock Young, Mohammad Shadab Siddiqui, Carolyn S.P. Lam, Yibin Wang, Gemma A. Figtree, Mark Y. Chan, David E. Cummings, Mazen Noureddin, Vincent Wai-Sun Wong, Ronald Ching Wan Ma, Christos S. Mantzoros, Arun Sanyal, Mark Dhinesh Muthiah
Journal: Cell Metabolism (2023)